Abstract

Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS), and majority of PCNSL is pathologically classified as diffuse large B-cell lymphoma (DLBCL). We have now performed whole-exome sequencing for 41 tumor tissues of DLBCL-type PCNSL and paired normal specimens and also RNA-sequencing for 30 tumors, revealing a very high frequency of nonsynonymous somatic mutations in PIM1 (100 %), BTG2 (92.7 %), and MYD88 (85.4 %). Many genes in the NF-κB pathway are concurrently mutated within the same tumors. Further, focal deletion or somatic mutations in the HLA genes are associated with poor prognosis. Copy number amplification and overexpression of genes at chromosome 7q35 were both found to predict short progression-free survival as well. Oncogenic mutations in GRB2 were also detected, the effects of which in cultured cells were attenuated by inhibitors of the downstream kinases MAP2K1 and MAP2K2. Individuals with tumors positive for MYD88 mutations also harbored the same mutations at a low frequency in peripheral blood mononuclear cells, suggesting that MYD88 mutation-positive precancerous cells originate outside of the CNS and develop into lymphoma after additional genetic hits that confer adaptation to the CNS environment.

Keywords

Primary central nervous system lymphoma Oncogene Genomics MYD88

Electronic supplementary material

The online version of this article (doi:10.1007/s00401-016-1536-2) contains supplementary material, which is available to authorized users.

Notes

Acknowledgments

This study was supported in part by a grant for Applied Research for Innovative Treatment of Cancer from the Ministry of Health, Labor, and Welfare of Japan, by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by a Research Grant from Princess Takamatsu Cancer Research Fund. We thank J. Shibahara, K. Suzuki, M. Tamura, and A. Maruyama for technical assistance. Raw sequencing data for exome and RNA-seq analyses have been deposited at the Japanese Genotype–Phenotype Archive (JGA, http://trace.ddbj.nig.ac.jp/jga), which is hosted by DDBJ, under the accession number JGAS00000000021.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.